The main objective of this project is the development and evaluation of small animal SPECT (single photon emission computed tomography) using skew-slit collimators. The state-of-the-art configuration for small animal SPECT imaging uses a pinhole or a multi-pinhole collimator. We propose the use of a skew-slit collimator to replace the pinhole or multi-pinhole collimator, in order to significantly reduce image artifacts and increase transaxial resolution. A pinhole forms a cone-beam imaging geometry. If the collimator rotates around the object (e.g., a small animal) in a circular orbit, the projection measurements acquired by the cone-beam imaging geometry are incomplete and not enough for an artifact-free image reconstruction. The severity of the artifact is proportional to the cone-angle of the pinhole in the direction of the axis of rotation. By transforming a pinhole into a pair of skew slits, the imaging cone-angle can be controlled by the distances of the two slits to the detector. We are able to use a large cone-angle in the transaxial direction to increase image magnification, and a small cone-angle in the direction of axis of rotation in order to reduce the data-insufficiency artifacts. This is achieved by placing a vertical slit (that is, the slit is parallel to the axis of rotation) close to the object and placing a horizontal slit farther out. The multi-pinhole collimator is able to significantly reduce the cone-beam artifacts and to increase the detection sensitivity by tiling the detector with multiple cone-beam images. To avoid multiplexing as much as possible, the cone-beam image magnification in the multi-pinhole collimator is smaller than that in the single- pinhole. The smaller image magnification could result in poorer spatial resolution. We therefore propose a multiple-skew-slit collimator that has one vertical slit and several horizontal slits. Compared with the multi- pinhole system, the multi-skew-slit system has a larger image magnification in the transaxial direction, and thus has better image resolution. This grant application promotes the development of very novel technologies in small animal imaging. While we show great potential for the skew-slit system in theory, further development of reconstruction algorithms and construction and testing of an actual physical system are required to move this idea into a lower risk category suitable for R01 type funding. A key goal is to generate preliminary data from a physical skew-slit system. Success in the aims here will provide evidence that skew-slit SPECT systems offer substantial improvements for small animal applications. The achievements will naturally form the basis for an R01 for rigorous evaluation and further optimization and improvements. PUBLIC HEALTH RELEVANCE: This project proposes a novel SPECT imaging system that has the potential to outperform the state-of-the-art pinhole imaging system. Our system uses perpendicular slits to replace the pinholes. As a result, the image resolution is improved. It means that we can see smaller objects. This new system will be very important in small animal imaging.